HistoryThis section has been translated automatically.
ADAM17 was the first "sheddase" to be identified. Thus, cloning of the TNF-α gene revealed that it encodes a 26 kDa type II transmembrane pro-polypeptide that is incorporated into the cell membrane during its maturation. Pro-TNF-α undergoes proteolytic cleavage, resulting in a soluble 17kDa extracellular domain (ectodomain). This soluble ectodomain is the cytokine known as TNF-α. This proteolytic cleavage of soluble TNF-α is catalyzed by ADAM17.
DefinitionThis section has been translated automatically.
The ADAM17 gene (ADAM17 stands for "A Disintegrin And Metalloproteinase 17") is a protein-coding gene located on chromosome 2p25.1.
The ADAM17 gene codes for the ADAM17 protein of the same name, which is also called TACE (tumor necrosis factor-α-converting enzyme), a 70 kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases (see also ADAM10).
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General informationThis section has been translated automatically.
ADAM family members are membrane-anchored proteins that are structurally related to snake venom disintegrins and are involved in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development and neurogenesis.
Members of the ADAM family are cell surface proteins with a unique structure that possess both potential adhesion and protease domains (sheddases). Sheddases primarily serve to cleave membrane proteins at the cellular surface. Once cleaved, the sheddases release soluble ectodomains with altered position and function (Moss ML et al. 2004; Nagano O et al. 2004).
The encoded protease is involved in ectodomain shedding of tumor necrosis factor-alpha, in which soluble tumor necrosis factor-alpha is released from the membrane-bound precursor. This process involves the cleavage and release of a soluble ectodomain of membrane-bound pro-proteins (such as pro-TNF-α) and is of known physiological importance.
ADAM17 is also involved in the processing of numerous other substrates, including cell adhesion proteins, cytokine and growth factor receptors, and epidermal growth factor (EGF) receptor ligands, and plays an important role in the activation of the Notch signaling pathway.
ADAM17 is responsible for the proteolytic release of soluble JAM3 from the surface of endothelial cells. Furthermore, the protease is responsible for the proteolytic release of several other cell surface proteins, including p75 TNF receptor, interleukin-1 receptor type II, p55 TNF receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein.
ADAM17 acts as an activator of the Notch signaling pathway by mediating the cleavage of Notch and thereby generating the membrane-associated intermediate fragment called "Notch extracellular truncation(NEXT)".
The protease plays a role in the proteolytic processing of ACE2 and further plays a role in hemostasis by cleaving GP1BA, the platelet glycoprotein Ib alpha chain.
ADAM17 (like ADAM10) mediates the proteolytic cleavage of LAG3 (lymphocyte activation gene 3), which leads to the release of the soluble form of LAG3.
ADAM17 mediates the proteolytic cleavage of IL-6R (interleukin-6 receptor, see IL6R gene below), which leads to the release of the soluble form of IL-6R.
Cellular localization: There are many indications that the majority of mature, endogenous ADAM17 is localized in a perinuclear compartment, with only a small amount present on the cell surface.
Clinical pictureThis section has been translated automatically.
ADAM17 deficiency is considered a very rare systemic autoinflammatory disease (de Jesus AA et al. 2015) characterized by autosomal recessive mutations in the ADAM17 gene encoding the TNF-α converting enzyme (TACE), a metalloprotease.
Functional ADAM17 has been shown to be ubiquitously expressed in the human colon, with increased activity in the colonic mucosa of patients with ulcerative colitis.
Furthermore, increased expression of the ADAM17 gene was observed in certain cell types of patients with psoriasis, rheumatoid arthritis, multiple sclerosis and Crohn's disease.
These findings suggest that the encoded protein could play a role in autoimmune diseases. In addition, this protease could play a role in viral infections through its cleavage of ACE2, the cellular receptor for SARS-CoV and SARS-CoV-2.
LiteratureThis section has been translated automatically.
Blaydon DC et al. (2011) Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med 365:1502-1508.
de Jesus AA et al. (2015) Molecular mechanisms in genetically defined autoinflammatory diseases: disordersof amplified danger signaling. Annu Rev Immunol 33:823-874
- Ludwig A et al. (2005) Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen 8:161-171.
- Palau V et al. (2019) Role of ADAM17 in kidney disease. Am J Physiol Renal Physiol 317:F333-F342.
- Scheller J et al. (2011) ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 32:380-387.
- Zunke F et al. (2017) The shedding protease ADAM17: Physiology and pathophysiology. Biochim Biophys Acta Mol Cell Res 1864:2059-2070.
